Deficit of beta cell mass and function occurs in all types of diabetes. The efforts to improve beta cell replacement therapy are compromised by persistent islet inflammation that either destructs beta cells or impairs their function. Our long-term goal is to develop novel approaches that can expand beta cells, while simultaneously protect beta cells from inflammatory insults. We have concentrated on pancreatic macrophages to understand their role in regulating islet inflammation and beta cell biology. In this proposal, we will explore a new mechanism to expand beta cells. Our preliminary studies have found that an epigenetic modulation targeting BET protein bromodomain enhances beta cell proliferation in vivo in animal models of type 1 diabetes. Our data strongly suggest that islet macrophages play a critical role in this process. These macrophages exhibit an elevated activation of PPAR-gamma pathway and also are immunosuppressive. Based on these findings, we propose that modulation of BET protein bromodomain reprograms islet macrophages to promote beta cell proliferation in an immunosuppressive islet environment. We will use animal models of type 1 diabetes, as well as human islet cultures to rigorously assess this novel strategy to expand beta cells in vitro and in vivo. The overall objective of this proposal is to gain an in-depth mechanistic view of this novel epigenetic modification strategy in expanding functional beta cells in a ?protective? islet microenvironment. We will address our goal in the framework of three specific aims. Aim 1 will specifically focus on exploring the role of PPAR-gamma pathway activation in macrophages for these cells to promote beta cell proliferation. In Aim 2, we will determine what factors are involved in macrophage-mediated beta cell proliferation, with a focus on PDGF signaling. In Aim 3, we will determine whether macrophage-mediated immunosuppression is a mechanism to promote beta cell functional recovery under autoimmune conditions. Successful completion of these aims will significantly advance our understanding of the novel roles of macrophages in beta cell biology. This study will pave a new way to expand functional beta cells for diabetes treatment.